Lercanidipine (methyl 1,1,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate) is a highly lipophilic dihydropyridine calcium antagonist with a long duration of action and high vascular selectivity. Lercanidipine's biological activity derives from its ability to competitively antagonize the dihydropyridine subunit of the L-type calcium channel.
Lercanidipine is useful as an anti-hypertensive. Lercanidipine lowers blood pressure by blocking calcium channels of arterial smooth muscle, thus decreasing peripheral vascular resistance. Lercanidipine produces no negative cardiac inotropism and only occasional mild reflex tachycardia, which is generally of short duration. Lercanidipine has been approved for the treatment of hypertension and has been marketed since 1996 in several European countries under the trademark Zanidip™.
The hydrochloride salt of lercanidipine is commercially available from Recordati S.p.A. (Milan, Italy). Methods of preparing lercanidipine hydrochloride, as well as methods of resolving lercanidipine into individual enantiomers are described in U.S. Pat. Nos. 4,705,797; 5,767,136; 4,968,832; 5,912,351; and 5,696,139, 6,852,737 and U.S. application, Publication No. 2003/0083355, all of which are incorporated herein by reference.
U.S. Pat. No. 4,705,797 described a process for the preparation of lercanidipine, the final step of the process being a cyclisation between 1,1,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl α-acetyl-3-nitrocinnammate and methyl 3-aminocrotonate. The lercanidipine was isolated as its hydrochloride salt by crystallization from water containing HCl and NaCl. However, this process was expensive, time consuming, and resulted in relatively low yields of lercanidipine hydrochloride. Accordingly, the disclosed method was poorly suited for commercial production of amorphous lercanidipine hydrochloride.
In addition to being poorly suited for commercialization, the lercandipine produced by the method of the '797 patent was a crude ill-defined mixture of amorphous lercanidipine hydrochloride containing from 1% to 2% of crystalline lercanidipine hydrochloride. The product had a hydration ratio of from about 0.3:1 to 0.5:1, and contained less than 95% of lercanidipine hydrochloride (including that in crystalline form). Such a product is too impure for pharmaceutical use, and would require extensive further purification, e.g., by chromatography on different phases, before it would be suitable for such use. However, purification by these methods is costly and time consuming to be commercially applicable and thus unsuitable for commercial application.
Co-pending U.S. application Ser. No. 11/244,315 discloses that amorphous compositions, and in particular amorphous lercanidipine free base, are well suited for use in modified release capsules comprising waxy substances. To facilitate the development of lercanidipine pharmaceutical compositions, there remains a need in the art for amorphous lercanidipine hydrochloride that is suitable for formulation in pharmaceutical preparations. There further remains a need in the art for methods of producing the pharmaceutical grade amorphous lercanidipine hydrochloride that are more efficient than prior art methods of making amorphous lercanidipine hydrochloride, and which yields amorphous lercanidipine hydrochloride that is substantially pure, easily handled and easily incorporated into pharmaceutical compositions and oral dosage forms, and which is practicable for practicing on an industrial scale. Additionally, it is preferred that the resulting amorphous lercanidipine hydrochloride have similar or improved characteristics, e.g., solubility and bioavailability, compared to lercanidipine hydrochloride of the prior art.
To facilitate the development of new pharmaceutical compositions and solid dosage forms, the present inventors have discovered an improved method of preparing amorphous lercanidipine hydrochloride that is rapid, simple, well-suited for production on a commercial scale and yields a substantially pure product. The purified amorphous lercanidipine hydrochloride of the invention which can be prepared by methods of the invention is well suited for incorporation into pharmaceutical compositions and solid dosage forms, particularly modified release pharmaceutical dosage forms comprising a waxy matrix as a release modifying agent.
The inventors have also discovered that the amorphous lercanidipine of the present invention may be advantageously incorporated into immediate release pharmaceutical compositions that have improved pharmacokinetic properties and consequently provide rapid reduction in hypertension when administered to a patient. Amorphous lercanidipine hydrochloride begins exerting its activity to reduce blood pressure within a period of time following its administration that is markedly shorter than the time required for obtaining an effect following administration of crystalline lercanidipine hydrochloride.